Despite long-term investment, influenza continues to be a significant worldwide problem. Influenza A viruses (IAV) are significant human pathogens causing yearly epidemics and occasional pandemics. Past pandemics have resulted in significant morbidity and mortality. The 1918 influenza pandemic was thought to have resulted in the death of at least 675,000 people in the U.S. and 40 million people worldwide. Pandemics in 1957 and 1968, while less severe, were also of major public health importance. A novel influenza A virus of swine origin became pandemic in 2009, causing the first pandemic in 41 years. In addition, annual epidemic influenza cases are also very significant resulting in up to 49,000 deaths in the U.S. annually. Human volunteer influenza virus challenge studies are continuing at the NIH Clinical Center using both a 2009 influenza A/H1N1 virus and a 2012 influenza A/H3N2 virus under FDA-approved INDs. A healthy volunteer screening study continued at the Clinical Center to identify patients who will qualify and be available for current and future challenge studies. In addition, a long-term study consisting of a 2 year follow up of patients who participated in previous challenge studies also continued to enroll with the first patients completing their 2 years follow up. These clinical studies over the past year have also included Phase II challenge studies to evaluate novel therapeutic and vaccines. One study under a CRADA with Crucell/Johnson and Johnson is evaluating a novel monoclonal therapeutic antibody, while another Phase II study under a CRADA with SEEK completed enrollment this year to evaluate a novel universal influenza vaccine. We also continue to further develop the challenge model through the development of other seasonal influenza A and B challenge viruses and continued collaboration with DCR on the development of FLUPRO, a validated questionnaire for measuring the severity of influenza infections. In addition to these clinical studies we continued our collaborations with Rockefeller University, Stanford, FDA, and within NIAID to further study human influenza infection and how it relates to other viral infections. In addition, we have performed further analysis of data collected from the previously completed challenge studies has continued. We recently completed the first evaluation of naturally occurring HA stalk antibody as a correlate of protection and what role it plays as a disease predictor in comparison to hemagglutination inhibition (HAI) titer and neuraminidase titer. The influenza virus hemagglutinin (HA) surface glycoprotein is currently the primary target of all licensed vaccines for influenza and considered the dominant antigen to which individuals develop a humoral immune response. Until recently, antibodies to the antigenically and genetically variable head region of the HA have been the major focus of influenza serological studies and vaccine development, specifically antibodies that sterically inhibit hemagglutinin receptor binding, utilizing the hemagglutination inhibition (HAI) assay to assess antibody titers. Over the course of the past decade there has been more focus on discovery of antibodies that target the more conserved stalk (or stem) region of the HA. These antibodies can be broadly neutralizing across one of two groups of the 18 known influenza A virus (IAV) HA subtypes, Group 1, which includes seasonal human H1 and highly pathogenic avian H5, and Group 2, which includes seasonal H3 2016-2017 in the form of an avian H7N9 IAV epizootic. These broadly neutralizing anti-HA stalk antibodies have been hypothesized to have played a major role in the extinction of the previously circulating pre-pandemic seasonal H1N1 lineage after the 2009 H1N1pdm virus emerged. The possibility that these broadly neutralizing anti-stalk antibodies that bind to conserved epitopes of group 1 or group 2 HA stalk could elicit broadly protective responses have led a number of groups to investigate novel vaccines and therapeutics based on anti-stalk antibody technology. Broad protection in animal models with anti-stalk antibody based vaccines/constructs has been shown and some of these investigational products are in preparation for future clinical trial evaluation. In a secondary analysis of our challenge study participants we observed that naturally occurring anti-HA stalk antibody titers were more common than previously thought, and that naturally occurring anti-HA stalk antibody titers are not independent predictors of disease outcome, that they predict disease similarly to HAI titer, and confirmed that NAI titer seems to be the best identified predictor of disease reduction and correlate of protection in these studies.